Abstract
G protein-coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism and discuss the recently uncovered and important roles of lipids in these processes.
Highlights
Cells sense their environment through the plasma membrane–embedded receptors, which capture external stimuli and convert them to intracellular signaling cascades leading to appropriate cellular responses and subsequent physiological outcomes
Signal transduction via a G protein–coupled receptors (GPCRs) starts when ligand binding to the receptor triggers or stabilizes an active receptor conformation, permitting coupling to heterotrimeric guanine nucleotide–binding proteins (G proteins), which are composed of three distinct a, b, and g subunits
Both Ga-GTP and Gbg independently regulate the activity of diverse effectors (Fig. 1), such as transmembrane adenylate cyclases via Gas to convert ATP into cAMP and initiate protein kinase A (PKA)- and exchange protein directly activated by cAMP (Epac; a cAMP-regulated guanine nucleotide exchange protein for small GTPase Rap1)-dependent signaling pathways, phospholipase Cb (PLCb) via Gaq to hydrolyze phosphatidylinositol [4,5]-bisphosphate (PIP2) into diacylglycerol (DAG), and inositol [1,4,5]-trisphosphate (IP3) to release stored Ca21 and activate protein kinase C (PKC), and/ or channels such as G protein–activated inwardly rectifying K1 (GIRK) channels via Gbg, resulting in cell membrane hyperpolarization
Summary
G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. We emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism and discuss the recently uncovered and important roles of lipids in these processes Cells sense their environment through the plasma membrane–embedded receptors, which capture external stimuli and convert them to intracellular signaling cascades leading to appropriate cellular responses (e.g. proliferation, differentiation, death) and subsequent physiological outcomes. Back in the year 2005, it was unclear why these two peptide hormones or their bioactive and structurally similar synthetic N-terminal analogs, PTH1-34 and PTHrP1-36, bind
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
